The present invention relates to methods for using photodynamic therapy (PDT) to inhibit or suppress stenoses of arteriovenous (AV) access fistulas and grafts.
Patients suffering from chronic renal failure must typically receive dialysis treatment two to three times a week. The most widely used form of dialysis is hemodialysis. In hemodialysis, blood is pumped out of the patient""s body to an artificial kidney machine that removes waste and excess fluid from the blood. Treated blood is returned to the patient""s body.
An AV access is a subcutaneous access placed by minor surgery typically in the forearm to provide a site to connect hemodialysis needles. An AV access graft is a commonly used type of AV access for hemodialysis. FIG. 1 illustrates a typical AV access graft, which is created by attaching a graft 10 between a vein 12 and an artery 14.
A significant problem associated with AV access for long-term dialysis patients is frequent AV access failure. Primary patency rates for AV access are extremely low. [Hodges, C. H. et al, Longitudinal comparison of dialysis access methods: Risk factors for failure. J Vasc. Surgery December 1997] (reporting 1-year primary patency rates for AV access fistulas and polytetraflouroethylene (PTFE) AV access grafts at 43% and 41% respectively). A frequent cause of permanent peripheral hemodialysis AV access failure is vascular stenosis, which occurs most frequently at the venous anastomotic site. This stenosis is generally believed to be the result of a persistent injury condition that occurs at the venous anastomotic site as a result of the pressure differential that exists between the arterial and venous systems and the associated disruption in the local rheodynamics.
Traditionally, surgical procedures such as thrombectomy and balloon angioplasty have been used to treat stenosis of AV access sites. However, such traditional treatment methods have had dismal results. Although an access may be restored with traditional intervention, such as percutaneous translumenal angioplasty (PTA), repeated failure is likely due to the persistent nature of the injury condition. As a result, efforts to utilize balloon angioplasty to prophylactically prolong the patency of AV accesses have not demonstrated a significant prolongation of graft and fistula patency. Thus, there is a significant need for an improved method for effectively preventing or removing stenotic lesions associated with AV access, particularly those located in the vicinity of the venous anastomotic site.
PDT is a relatively new method that is under development for the treatment of various diseases including cancer, psoriasis, arterial plaques and restenosis, macular degeneration, glaucoma, and certain viral infections. The PDT procedure is conducted by administering a photosensitizer drug to the desired treatment zone, by either local or systemic means, followed by exposure to photoactivating light. The photoactivating light excites the photosensitizer, which in turn generates toxic species such as singlet oxygen, oxygen radicals, peroxide radicals or other radical species which generate a PDT effect, as is well known to those skilled in the art. These toxic species interact with tissues in which the photosensitizer is localized, resulting in modification or destruction of the tissue and the desired clinical effect.
In the case of arterial plaques and restenosis, PDT has been demonstrated in numerous animal models and has recently been introduced in a clinical study. One example of early work in this field is that done by Ortu et al. [Photodynamic Therapy of Arteries: A Novel Approach for Treatment of Experimental Intimal Hyperplasia, Circulation, 85: 1189-1196, March 1992]. In that study the injury usually associated with arterial restenosis was simulated and then treated with PDT in an effort to inhibit the development of intimal hyperplasia. During the past decade numerous other studies have been conducted in an effort to either inhibit the development of intimal hyperplasia in arteries or to reduce the plaque that has developed within an artery.
In contrast to the arterial system, only limited studies report the use of PDT for treatment of stenotic lesions within the venous system. Part of the reason for this is likely due to the very different biology associated with veins and arteries. Although both veins and arteries serve as blood conduits, their structure and biological response mechanisms are significantly different. For example, in the case of AV access, the stenoses occurring in the anastomotic region has been hypothesized to arise, at least in part, from the pressure differential between the arterial and venous systems, as well as from turbulence that exists near the anastomotic sites. Such conditions do not exist in the standard arterial injuries for which PDT has previously been investigated. Similarly, they do not exist in the case of interpositional grafts such as those studied by LaMuraglia and described below. Given the different nature of the injury responsible for the stenosis in AV access as well as the lack, to date, of a safe and effective means of treating such stenoses, it has not been demonstrated whether a treatment used to treat intimal hyperplasia in arteries will inhibit or suppress stenotic lesions at the anastomosis in AV access sites.
LaMuraglia et al. [Photodynamic Therapy of Vein Grafts: Suppression of Intimal Hyperplasia of the Vein Graft but not the Anastomosis, J of Vascular Surgery, Vol. 21, No 6: June 1995] reports the use of PDT for the suppression of intimal hyperplasia in autologous vein grafts. In that work an autologous bypass graft in a rat model was treated with PDT in an effort to inhibit intimal hyperplasia. The rats were first given a systemic injection of a photosensitizer drug and at 24 hours after drug injection a section of the jugular vein was surgically removed. Following removal, the harvested vein section received light treatment (ex-vivo) to induce the PDT effect. This vein section was then used as an interpositional graft of the carotid artery of the animal from which it had been harvested. This was done by first removing a short section of carotid artery, then suturing the section of treated vein into its place, oriented properly for blood flow. Results of this study did not provide any measurable inhibition of the intimal hyperplasia occurring at the anastomosis at either end of the interpositional graft.
The results noted in LaMuraglia et al. suggest that their treatment method would not be an effective treatment for AV access sites, since the most common location of stenosis is at the venous anastomosis site [Chapter 74: Arteriovenous Grafts in Vascular Diseases: Surgical and Interventional Therapy, Churchill Livingstone Publishers, January 1994, pg. 1055-1062, ISBN: 0443088411]. Specifically, LaMuraglia""s approach, consisting of ex-vivo treatment of the graft but not the anastomosis, failed to demonstrate a viable graft as a result of the formation of stenosis at the anastomosis site.
Based on the lack of success with previous approaches, there exists a strong need for an effective method of treating stenoses in AV access fistulas and grafts. While PDT has been shown to be a promising treatment for inhibiting or suppressing stenosis associated with intimal hyperplasia in arteries, similar results have not been demonstrated in the treatment of stenosis in AV access fistulas and grafts. Furthermore no method has been demonstrated to effectively reduce stenosis of AV access fistulas or grafts while safely preserving the viability of the vessel at the site of the anastomosis.
The present invention relates to a method for safely and effectively inhibiting or suppressing stenosis associated with an arteriovenous access connecting an artery and a vein, each having an anastomotic area. At least one of the blood vessels is contacted with a photosensitive compound (e.g., by local or systemic administration). Target tissue which includes the anastomotic area of the contacted blood vessel is exposed to a source of light having a wavelength suitable for photoactivating the photosensitive compound for a period of time sufficient to provide a therapeutic effect.
In the case of inhibiting stenosis formation, the anastomotic area can be exposed to the source of light either before or after graft implantation or creation of the fistula. For existing lesions, the light can also be delivered transcutaneously if the drug is delivered locally. In one embodiment, the photosensitizer drug is endolumenally incubated in the blood vessel for a sufficient time to allow the compound to diffuse into the blood vessel. In a second embodiment, the photosensitzer drug is administered into the isolated portion of the blood vessel using transcutaneous access via the graft, adjacent artery or adjacent vein. In a third embodiment, the photosensitizer drug is administered systemically via intravenous delivery. In a fourth embodiment, the photosensitizer drug is delivered directly to the target site using a local drug delivery device.
Alternatively, a sleeve or cuff may be placed around the surgically exposed blood vessel for incubating the photosensitive compound within the sleeve or cuff so that the photosensitizer drug is kept in contact with a wall of the blood vessel for a sufficient time to allow the compound to diffuse into the vessel wall.
The dosage of photosensitive compound may also be administered by applying a semisolid substance (e.g., a gel-like substance or paste) containing the photosensitizer drug directly to the wall of the blood vessel.
Light treatment can be delivered to the anastomotic area of the blood vessel using either an intralumenal light delivery catheter or using an external light delivery device.
A shield can be placed between the irradiation site encompassing the vessel anastomosis and the surrounding tissue during light exposure to prevent excitation of any drug in surrounding tissue. Alternatively, a cuff or sleeve that limits light transmission can be implanted around the graft or anastomotic area of the blood vessel at the time of graft implantation to allow later intralumenal light treatment using a deeply penetrating wavelength of light without exposing the tissue surrounding the graft.